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Selenoprotein N‐Related Myopathy

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Selenoprotein N‐Related Myopathy RESEARCH ARTICLE Selenoprotein N-related myopathy: a retrospective natural history study to guide clinical trials Arpana Silwal1,a , Anna Sarkozy1,a, Mariacristina Scoto1,a, Deborah Ridout2,7, Anne Schmidt3, Aidan Laverty3, Matilde Henriques3, Luigi D’Argenzio1, Marion Main1, Rachael Mein4, Adnan Y Manzur1, Francois Abel3, Fouad Al-Ghamdi5, Casie A Genetti5, Didem Ardicli6, Goknur Haliloglu6, Haluk Topaloglu6, Alan H Beggs5 & Francesco Muntoni1,7 1The Dubowitz Neuromuscular Centre, Developmental Neuroscience Program, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, London, UK 2Population, Policy and Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK 3Respiratory Department, Sleep and Non-Invasive Ventilation, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK 4Genetic Department, Molecular Genetics Laboratory Viapath, Guy’s Hospital, London, UK 5Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA 6Hacettepe University Children’s Hospital, Department of Paediatric Neurology, Ankara, Turkey 7NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, Great Ormond Street Hospital Trust, London, UK Correspondence Abstract Francesco Muntoni, Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Objective: To describe clinical features and disease progression of Selenopro- Child Health, 30 Guilford Street, London tein N-related myopathy in a large multicenter cohort of patients. Methods: WC1N 1EH. Tel: +44 02079052111; Fax: +44 Cross-sectional multicenter data analysis of 60 patients (53 families) with 02079052832; E-mail: [email protected] Selenoprotein N-related myopathy and single-center retrospective longitudinal analysis of 25 patients (21 families) over a median period of 5.3 years. Results: Funding Information The majority of patients (46/60, 77%) presented before age 2 years with hypo- This work was supported in part by The Muscular tonia, poor head/neck control, and developmental delay. At last assessment Dystrophy UK Central Grant to the DNC and by (median age 14 years; range 2.5 to 36 years), 10/60 patients had minimal or no grant MDA602235 from the Muscular Dystrophy ambulation. Ventilatory support was initiated in 50/60 patients at a mean Association (USA) and a generous gift from the Lee and Penny Anderson Family Foundation. Forced Vital Capacity (FVC) of 38% and at a median age of 13 years. Forty- Diagnostic DNA sequencing of patients in the five/60 patients developed scoliosis (at median age 12.1 years) and 18 had scol- Boston cohort utilized the resources of the iosis surgery at a median age of 13.6 years. Five children needed nasogastric Boston Children’s Hospital IDDRC Molecular feeds and/or gastrostomy. Longitudinal data analysis on 25 patients showed Genetics Core Laboratory funded by progressive decline of Hammersmith functional motor scores (estimated annual U54HD090255 from the US National Institutes of change À0.55 point), time to walk 10 meter, time standing from sitting, and Health. This research was also supported by the from lying. Sixteen patients had weights < 2nd centile. The estimated change in NIHR Great Ormond Street Hospital Biomedical À À À Research Centre. The views expressed are those FVC % per year was 2.04, with a 95% CI ( 2.94, 1.14). Conclusions: This of the author(s) and not necessarily those of the comprehensive analysis of patients with Selenoprotein N-related myopathy fur- NHS, the NIHR, or the Department of Health. ther describes the clinical course of this rare condition. The observed functional motor and respiratory data provide evidence of the slow decline patients experi- Received: 26 June 2020; Revised: 15 ence over time which is useful when considering therapeutic intervention. September 2020; Accepted: 20 September 2020 doi: 10.1002/acn3.51218 aThese authors equally contributed to the manuscript. ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association 1 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Natural History of Selenoprotein N-related Myopathy A. Silwal et al. Introduction patients were previously reported.6,8 All patients had a molecularly confirmed diagnosis of SELENON-RM with Selenoprotein N-related myopathies are recessive condi- two pathogenic SELENON variants in trans, identified tions caused by pathogenic variants in the SELENON 1-3 either by Sanger sequencing or next-generation sequenc- gene (previously known as SEPN1). The disease spec- ing (Table S1). trum includes congenital muscular dystrophy (CMD) Cross-sectional data were collected for 60 patients. with rigid spine, multiminicore disease, desmin-related Clinical data for patients from site N1 and N2 were col- myopathy with Mallory body-like inclusions and congen- 3-6 lected using a comprehensive medical questionnaire ital fiber-type disproportion myopathy, all sharing the (Table S2). Clinical data for patients from Site N3 were primary features of early-onset muscle weakness affecting available for more than one time-point and thus the most axial muscles, leading to early respiratory insufficiency.7-8 recent value was used for cross-sectional analysis, to make Selenoprotein N-related myopathies (SELENON -RM) 9 the information comparable among the three sites. are estimated to account for 11.65% of CMDs and 16% 10 Retrospective longitudinal clinical data were collected of congenital myopathies (CM) in the UK. The inter- 11,12 for patients from Site N3 only for the following parame- national standards of care for CMD and CM recom- ters: weight, motor function, respiratory function, and mend multidisciplinary follow-up for SELENON -RM Cobb angle. Motor function tests included The Hammer- and management of respiratory and orthopedic compli- smith standardized functional motor scores (HFMS),15 cations. timed 10 meters walk, timed raising from sitting, and Selenoprotein N, the protein product of the SELENON lying. Respiratory function measurements included gene, localizes in the endoplasmic/sarcoplasmic reticulum spirometry (forced vital capacity, FVC), performed in a (ER/SR) and interacts with SERCA2, the SR/ER pediatric lung function laboratory by experienced opera- Ca2 + pump, to keep it active within the relatively oxidizing 13 tors. The Global Lung Initiative dataset was used for ref- environment of the SR. The absence of Selenoprotein N erence.16 Sleep studies were performed in a pediatric sleep leads to a maladaptive ER stress response by oxidizing and 14 laboratory. Sleep-disordered breathing (SDB) was scored inhibiting SERCA2, adversely affecting muscle function. according to a standardized scoring system17. The use of ER stress inhibitors is being investigated as a pos- The project followed Caldicott Guardian regulations sible treatment for SELENON-RM and a clinical trial with and only anonymized de-identified aggregated patient N-acetylcysteine is ongoing (NCT02505087). Improved data were shared between the three sites. understanding of the pathogenesis of this condition fol- lowed by early therapeutic trials, make it necessary to better define the natural history and identify clinical endpoints to Statistical Methods support clinical trial readiness. Currently, no longitudinal Summaries are presented at the latest follow-up visit with SELENON studies on -RM have been reported. mean and standard deviation for normally distributed This study aims to provide deep phenotypic analysis data, and median and interquartile range for skewed data. and description of the disease course in a large multicen- For the cross-sectional cohort, Kaplan–Meier estimates SELENON ter cohort of -RM patients. In particular, we were calculated to describe the median time to scoliosis analyzed progression over time of motor abilities, respira- and ventilation. Frequency data are presented along with tory function, and scoliosis, aiming to identify clinical proportions and comparisons between groups, for exam- parameters to guide clinicians on disease timeline, and ple, diagnosis before or after 2 years of age were made provide information on prognosis, anticipatory care, and using a chi-squared test. For the longitudinal cohort tra- trajectories of functional changes, to help developing out- jectories for functional motor score, respiratory function, come measures for future clinical trials. and weight centiles over time were modeled using mixed- effects regression, accounting for the repeated measures Methods within patients. Estimated slopes are presented along with 95% confidence intervals. All statistical analyses were con- Sixty patients from (51 families) with SELENON-RM ducted in Stata v 15 (StataCorp. 2017. Stata Statistical were enrolled from three clinical sites: Site N1, Beggs Software: Release 15. College Station, TX: StataCorp LLC) Laboratory Congenital Myopathy Research Program, and a p value < 0.05 was deemed significant. Boston Children’s Hospital (Boston Children’s Hospital IRB protocol: 03-08-128) (22 patients) Site N2, Hacet- Results tepe University Children’s Hospital, Turkey (13 patients); and Site
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